1. Field of the Invention
The present invention relates to amidite derivatives having a monosaccharide or a derivative thereof at their terminals. In particular, the present invention relates to oligonucleotide derivatives in which oligonucleotides are introduced into said amidite derivatives.
2. Description of the Related Art
In recent years, attempts have been made to suppress the expression of targeted genes using oligonucleotides, specifically antisense oligonucleotides. However, it was found that when administered directly into the body, the oligonucleotides were readily decomposed in the blood, or the greater portion was readily excreted in the urine. Moreover, the nucleotides were decomposed or excreted without being incorporated into the targeted cells of lesioned organs.
To resolve these problems, it has been reported that the formation of a conjugate of asialoorosomucoid with poly-L-lysine yields a complex which ionically interacts with the antisense oligonucleotide of human hepatitis B virus and the ionic complex enhanced the inhibitory effect of the antisence oligodeoxynucleotide on the biosynthesis of viral protein significantly (G. Y. Wu and C. H. Wu (1992) J. Biol. Chem. 267, 12436) and that the chloramphenicol acetyltransferase gene can be transferred into and expressed in the liver using a similar complex (G. Y. Wu and C. H. Wu (1991) Biotherapy 3, 879). Techniques used in these reports are described in WO 93/04701 and 92/20316. Furthermore, it is reported in WO 93/19768 that a complex formed between DNA and a saccharide derivative, which was covalently coupled with a molecule to intercalate into DNA by inserting in the double helix structure (i.e. intercalator) was incorporated into a cell which specifically recognized the saccharide such that it was useful for the efficient expression of genetic information. Nakai et al intravenously injected an antisense nucleic acid complex, and a simulation of the amount delivered into the liver showed that this type of non-covalently bonded complex easily dissociates in the blood to preclude any significant transfer into the liver (D. Nakai, T. Seita and Y. Sugiyama (1995) Pharm. Tech. Japan, 11, 27).
On the other hand, it is known that a compound in which galactose is introduced into carboxymethylated dextran (M. Nishikawa et al. (1993) Pharmaceutical Research 10, 1253), and a compound in which galactose is introduced into poly-L-glutamic acid are selectively distributed in hepatocytes (H. Hirabayashi et al (1994) Proceedings of the General Presentation of the 144th Annual Meeting of Japan Pharmacological Association 30(6) 15-4).